2. Academic Validation
  3. Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

  • Eur J Med Chem. 2024 Sep 10:279:116853. doi: 10.1016/j.ejmech.2024.116853.
Shanyun Gao 1,  Yingjie Hou 1,  Yanxiao Xu 1,  Jingjing Li 1,  Chaobo Zhang 1,  Shujuan Jiang 1,  Songda Yu 1,  Lei Liu 1,  Wangyang Tu 2,  Bing Yu 3,  Yixiang Zhang 4,  Leping Li 5
Affiliations

Affiliations

  • 1 Discovery & Early Development, Haihe Biopharma Co., Ltd., No 865, Zuchongzhi Road, Zhangjiang Science City, Shanghai, 201203, China.
  • 2 Discovery & Early Development, Haihe Biopharma Co., Ltd., No 865, Zuchongzhi Road, Zhangjiang Science City, Shanghai, 201203, China. Electronic address: wangyang.tu@haihepharma.com.
  • 3 Discovery & Early Development, Haihe Biopharma Co., Ltd., No 865, Zuchongzhi Road, Zhangjiang Science City, Shanghai, 201203, China. Electronic address: bing.yu@haihepharma.com.
  • 4 Discovery & Early Development, Haihe Biopharma Co., Ltd., No 865, Zuchongzhi Road, Zhangjiang Science City, Shanghai, 201203, China. Electronic address: yixiang.zhang@haihepharma.com.
  • 5 Discovery & Early Development, Haihe Biopharma Co., Ltd., No 865, Zuchongzhi Road, Zhangjiang Science City, Shanghai, 201203, China. Electronic address: leping.li@haihepharma.com.
PMID: 39270452 DOI: 10.1016/j.ejmech.2024.116853
Abstract

Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is the dominant hydrolase of 2',3'-cyclic GMP-AMP (cGAMP). Inhibition of ENPP1 contributes to increased cGAMP concentration and stimulator of interferon gene (STING) activation, with the potential to boost immune response against Cancer. ENPP1 is a promising therapeutic target in tumor immunotherapy. To date, orally bioavailable ENPP1 inhibitors with highly potent activity under physiological conditions have been rarely reported. Herein, we report our effort in the design and synthesis of two different series of ENPP1 inhibitors, and in the identification of a highly potent ENPP1 inhibitor 27 (IC50 = 1.2 nM at pH 7.5), which significantly enhanced the cGAMP-mediated STING activity in THP-1 cells. Phosphonate compound 27 has good preclinical pharmacokinetic profiles with low plasma clearance rate in mouse, rat, and dog. It has been developed as bis-POM prodrug 36 which successfully improves the oral bioavailability of 27. In the Pan02 syngeneic mouse model of pancreatic Cancer, orally administered 36 showed synergistic effect in combination with radiotherapy.

Keywords

ENPP1 inhibitor; Phosphonate prodrugs; STING pathway; Tumor immunotherapy.

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